COG1-congenital disorder of glycosylation

Mendelian MONDO:0012637 Pathograph 45 Show in embeddings browser congenital disorder of glycosylation type II developmental anomaly of metabolic origin defect in conserved oligomeric Golgi complex

COG1-congenital disorder of glycosylation is an extremely rare autosomal recessive congenital disorder of glycosylation type II caused by biallelic COG1 variants. COG1 deficiency disrupts the conserved oligomeric Golgi complex, impairs intra-Golgi trafficking and glycosylation-enzyme localization, and causes a multisystem neurodevelopmental syndrome with abnormal N- and O-glycosylation.

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1
Inheritance
10
Pathophys.
29
Phenotypes
45
Pathograph
1
Genes
3
Medical Actions
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Reported COG1-CDG patients have biallelic COG1 variants, including homozygous frameshift variants and compound heterozygous splice/missense variants.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:16537452 SUPPORT Human Clinical
"Sequence analysis of the COG1 cDNA and gene identified a homozygous insertion of a single nucleotide (2659–2660insC), which is predicted to lead to a premature translation stop and truncation of the C terminus of the Cog1 protein by 80 amino acids."
The discovery report identifies a homozygous truncating COG1 variant in the affected patient.
PMID:34625039 SUPPORT Human Clinical
"Genetic analysis showed that the patient carried the heterozygous intron mutation c.1070 + 3A > G (splicing) in the coding region of the COG1 gene that was inherited from the mother, and the heterozygous mutation c.2492G > A (p. Arg831Gln) in exon 10 of the COG1 gene that was inherited from the father."
This case report supports biallelic COG1 involvement through compound heterozygous inherited variants.
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Pathophysiology

10
COG1 Deficiency Disrupts the Conserved Oligomeric Golgi Complex
Pathogenic COG1 variants impair function of the conserved oligomeric Golgi complex, disrupting intra-Golgi trafficking and the localization or stability of Golgi glycosylation enzymes.
COG1 hgnc:6545 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COG1 (hgnc:6545). hgnc:6545 is a gene from the HUGO Gene Nomenclature Committee.
Golgi vesicle transport GO:0048193 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Golgi vesicle transport (GO:0048193). GO:0048193 is a biological process from the Gene Ontology. ⚠ ABNORMAL intra-Golgi vesicle-mediated transport GO:0006891 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal intra-Golgi vesicle-mediated transport (GO:0006891). GO:0006891 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Golgi apparatus GO:0005794 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Golgi apparatus (GO:0005794). GO:0005794 is an anatomical location from the Gene Ontology.
Downstream
Retrograde Golgi trafficking delay COG1 splice or truncating defects can delay retrograde trafficking in patient fibroblasts.
Defective N- and O-glycosylation COG-complex disruption alters Golgi glycosylation-enzyme localization, causing combined N- and O-glycosylation defects.
Show evidence (1 reference)
PMID:16537452 SUPPORT In Vitro
"This mutation destabilizes several other COG subunits and alters their subcellular localization and hence the overall integrity of the COG complex."
Patient-derived molecular evidence directly links the COG1 truncating variant to COG-complex instability and altered subcellular localization.
Retrograde Golgi trafficking delay
COG1 deficiency impairs retrograde vesicular trafficking through the Golgi, disrupting the trafficking environment needed to maintain glycosylation enzyme localization and glycan processing.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Golgi vesicle transport GO:0048193 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Golgi vesicle transport (GO:0048193). GO:0048193 is a biological process from the Gene Ontology. ⚠ ABNORMAL intra-Golgi vesicle-mediated transport GO:0006891 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal intra-Golgi vesicle-mediated transport (GO:0006891). GO:0006891 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Golgi apparatus GO:0005794 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Golgi apparatus (GO:0005794). GO:0005794 is an anatomical location from the Gene Ontology.
Downstream
Defective N- and O-glycosylation Retrograde trafficking abnormalities impair maintenance of Golgi glycosylation machinery, producing the combined glycosylation defect.
Show evidence (2 references)
PMID:19008299 SUPPORT In Vitro
"This hetero-octameric protein complex is involved in retrograde vesicular trafficking and glycosylation."
The COG1 cerebrocostomandibular-like syndrome report places the COG complex in retrograde trafficking and glycosylation.
PMID:19008299 SUPPORT In Vitro
"A delay in retrograde trafficking could be demonstrated by Brefeldin A treatment of this patient's fibroblasts."
Brefeldin A testing demonstrates delayed retrograde trafficking in patient fibroblasts.
Defective N- and O-glycosylation
Disrupted Golgi trafficking impairs glycoprotein processing, producing a type II CDG pattern with combined N-linked and O-linked glycosylation abnormalities.
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ↓ DECREASED protein O-linked glycosylation GO:0006493 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein O-linked glycosylation (GO:0006493). GO:0006493 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Abnormal serum N- and O-glycan processing Combined glycosylation impairment produces abnormal serum N-glycan sialylation/galactosylation and abnormal mucin-type O-glycan sialylation.
Type II Transferrin Isoform Profile Defective Golgi glycosylation can be detected clinically as a type II transferrin isoform profile.
Failure to Thrive Orphanet records failure to thrive as part of the multisystem COG1-CDG phenotype spectrum.
Neurological involvement COG1-CDG glycosylation defects are associated with developmental delay and seizures or convulsions in reported patients.
Craniofacial dysmorphism involvement COG1-CDG glycosylation defects are associated with dysmorphism in a reported neonatal presentation.
Ocular alignment involvement COG1-CDG glycosylation defects are associated with strabismus in a reported compound heterozygous case.
Hepatic involvement Reported patients can show hepatitis as a hepatic manifestation of COG1-CDG.
Hypoglycemia susceptibility Reported patients can show hypoglycemia as a metabolic manifestation.
Costovertebral skeletal involvement A COG1 splice-variant presentation included costovertebral dysplasia as a skeletal manifestation.
Abnormal Macular Morphology Orphanet records abnormal macular morphology as a frequent manifestation of COG1-CDG.
Pulmonary Arterial Hypertension Orphanet records pulmonary arterial hypertension as a frequent manifestation of COG1-CDG.
Postnatal Growth Retardation Orphanet records postnatal growth retardation as a frequent manifestation of COG1-CDG.
Atrial Septal Dilatation Orphanet records atrial septal dilatation as a frequent manifestation of COG1-CDG.
Show evidence (3 references)
PMID:16537452 SUPPORT Human Clinical
"This patient has a defect in both N- and O-glycosylation."
The abstract directly states the combined N- and O-glycosylation defect in the COG1-CDG patient.
PMID:16537452 SUPPORT Human Clinical
"Mass spectrometric analysis of the structures of the N-linked glycans released from glycoproteins from the patient's serum revealed a reduction in sialic acid and galactose residues."
Serum glycan mass spectrometry supports abnormal N-glycan processing in the affected patient.
PMID:16537452 SUPPORT In Vitro
"Peanut agglutinin (PNA) lectin staining revealed a decrease in sialic acids on core 1 mucin type O-glycans, indicating a combined defect in N- and O-glycosylation."
PNA lectin staining supports the O-glycosylation component of the combined glycosylation defect.
Abnormal serum N- and O-glycan processing
Patient serum and lectin assays show reduced sialic acid and galactose on N-glycans and reduced sialylation of core 1 mucin-type O-glycans, producing the type II CDG biochemical signature.
Show evidence (2 references)
PMID:16537452 SUPPORT Human Clinical
"Mass spectrometric analysis of the structures of the N-linked glycans released from glycoproteins from the patient's serum revealed a reduction in sialic acid and galactose residues."
This directly supports abnormal serum N-glycan processing.
PMID:16537452 SUPPORT In Vitro
"Peanut agglutinin (PNA) lectin staining revealed a decrease in sialic acids on core 1 mucin type O-glycans, indicating a combined defect in N- and O-glycosylation."
This directly supports abnormal mucin-type O-glycan sialylation.
Neurological involvement
The reported COG1-CDG neurological spectrum includes developmental delay and neonatal seizures or convulsions.
Downstream
Global developmental delay Developmental retardation is one of the main reported clinical symptoms.
Seizures Seizures or convulsions are reported neurologic manifestations.
Mild Intellectual Disability
Cerebellar Vermis Hypoplasia
Enlarged Cisterna Magna
Show evidence (2 references)
PMID:34625039 SUPPORT Human Clinical
"The patient was male, and the main clinical symptoms were developmental retardation, convulsion, strabismus, and hypoglycemia, which is rarely reported in CDG-IIg."
This COG1-CDG case report supports developmental delay and convulsions.
PMID:33960418 SUPPORT Human Clinical
"We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing."
The review abstract supports neonatal seizures in a reported patient.
Craniofacial dysmorphism involvement
Dysmorphism is reported as a craniofacial manifestation in COG1-CDG.
Downstream
Dysmorphism Dysmorphism is reported in the neonatal COG1-CDG presentation.
Pierre-Robin Sequence Orphanet records Pierre-Robin sequence as a frequent craniofacial phenotype of COG1-CDG.
Thin Upper Lip Vermilion
Smooth Philtrum
Posteriorly Rotated Ears
Short Neck
Show evidence (1 reference)
PMID:33960418 SUPPORT Human Clinical
"We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing."
The review abstract supports dysmorphism in a reported COG1-CDG patient.
Ocular alignment involvement
Strabismus is reported as an ocular alignment manifestation in COG1-CDG.
Downstream
Strabismus Strabismus is reported among the main symptoms in a COG1-CDG case.
Show evidence (1 reference)
PMID:34625039 SUPPORT Human Clinical
"The patient was male, and the main clinical symptoms were developmental retardation, convulsion, strabismus, and hypoglycemia, which is rarely reported in CDG-IIg."
The case report supports strabismus in COG1-CDG/CDG-IIg.
Hepatic involvement
COG1-CDG can include hepatitis alongside the type II glycosylation defect.
Downstream
Hepatitis Hepatitis is a reported hepatic manifestation.
Show evidence (1 reference)
PMID:33960418 SUPPORT Human Clinical
"We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing."
This supports hepatitis in a reported COG1-CDG patient.
Hypoglycemia susceptibility
COG1-CDG can include hypoglycemia alongside the type II glycosylation defect.
Downstream
Hypoglycemia Hypoglycemia is reported as a main symptom and was responsive to glucose infusion in one case.
Show evidence (1 reference)
PMID:34625039 SUPPORT Human Clinical
"The patient was male, and the main clinical symptoms were developmental retardation, convulsion, strabismus, and hypoglycemia, which is rarely reported in CDG-IIg."
This supports hypoglycemia in a reported COG1-CDG patient.
Costovertebral skeletal involvement
Two COG1-mutated patients with the recurrent c.1070+5G>A splice variant were described with cerebrocostomandibular-like syndrome and costovertebral dysplasia, supporting a skeletal branch in this mutation class.
Downstream
Costovertebral dysplasia Costovertebral dysplasia is the reported skeletal manifestation in the two COG1 c.1070+5G>A patients.
Posterior Rib Gap Orphanet records posterior rib gap as a frequent skeletal phenotype of COG1-CDG.
Butterfly Vertebrae Orphanet records butterfly vertebrae as a frequent vertebral phenotype of COG1-CDG.
Rib Fusion
Irregularity of Vertebral Bodies
Short Long Bone
Rhizomelia
Osteopenia
Talipes Equinovarus
Show evidence (3 references)
PMID:19008299 SUPPORT Human Clinical
"We describe two patients with a cerebrocostomandibular-like syndrome and a novel mutation in conserved oligomeric Golgi (COG) subunit 1"
The abstract supports a cerebrocostomandibular-like skeletal presentation in COG1-mutated patients.
PMID:19008299 SUPPORT Human Clinical
"The costovertebral dysplasia of the two patients has been described in cerebrocostomandibular syndrome (CCMS), but also in cerebrofaciothoracic dysplasia and spondylocostal dysostosis."
The abstract directly supports costovertebral dysplasia in the two reported COG1-mutated patients.
PMID:19008299 SUPPORT Human Clinical
"We identified in both patients an intronic mutation, c.1070+5G>A, that disrupts a splice donor site and leads to skipping of exon 6, a frameshift and a premature stopcodon in exon 7."
This identifies the splice-variant class associated with the two costovertebral dysplasia patients.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for COG1-congenital disorder of glycosylation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

29
Cardiovascular 1
Pulmonary Arterial Hypertension FREQUENT HP:0002092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary arterial hypertension (HP:0002092). HP:0002092 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0002092 | Pulmonary arterial hypertension | Frequent (79-30%)"
Orphanet records pulmonary arterial hypertension as a frequent phenotype of COG1-CDG.
Digestive 1
Hepatitis HP:0012115 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatitis (HP:0012115). HP:0012115 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33960418 SUPPORT Human Clinical
"We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing."
The review abstract explicitly identifies hepatitis in a COG1-CDG patient.
Eye 1
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34625039 SUPPORT Human Clinical
"The patient was male, and the main clinical symptoms were developmental retardation, convulsion, strabismus, and hypoglycemia, which is rarely reported in CDG-IIg."
The case report directly lists strabismus in the affected patient.
Head and Neck 2
Dysmorphism Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33960418 SUPPORT Human Clinical
"We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing."
The review abstract explicitly reports dysmorphism in a COG1-CDG patient; the HPO term is a broad mapping for facial dysmorphism.
Short Neck FREQUENT HP:0000470 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short neck (HP:0000470). HP:0000470 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0000470 | Short neck | Frequent (79-30%)"
Orphanet records short neck as a frequent phenotype of COG1-CDG.
Limbs 1
Talipes Equinovarus FREQUENT HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0001762 | Talipes equinovarus | Frequent (79-30%)"
Orphanet records talipes equinovarus as a frequent phenotype of COG1-CDG.
Metabolism 1
Hypoglycemia HP:0001943 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoglycemia (HP:0001943). HP:0001943 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34625039 SUPPORT Human Clinical
"The patient was male, and the main clinical symptoms were developmental retardation, convulsion, strabismus, and hypoglycemia, which is rarely reported in CDG-IIg."
The case report explicitly lists hypoglycemia as a main symptom in COG1-CDG/CDG-IIg.
Musculoskeletal 2
Costovertebral dysplasia Abnormality of the vertebral column HP:0000925 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Costovertebral dysplasia, annotated with Abnormality of the vertebral column (HP:0000925). HP:0000925 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19008299 SUPPORT Human Clinical
"The costovertebral dysplasia of the two patients has been described in cerebrocostomandibular syndrome (CCMS), but also in cerebrofaciothoracic dysplasia and spondylocostal dysostosis."
The abstract directly supports costovertebral dysplasia; HP:0000925 is a broad mapping for the vertebral component of the skeletal phenotype.
PMID:19008299 SUPPORT Human Clinical
"We identified in both patients an intronic mutation, c.1070+5G>A, that disrupts a splice donor site and leads to skipping of exon 6, a frameshift and a premature stopcodon in exon 7."
This identifies the splice-variant class associated with the two costovertebral dysplasia patients.
Osteopenia FREQUENT HP:0000938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteopenia (HP:0000938). HP:0000938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0000938 | Osteopenia | Frequent (79-30%)"
Orphanet records osteopenia as a frequent phenotype of COG1-CDG.
Nervous System 4
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34625039 SUPPORT Human Clinical
"The patient was male, and the main clinical symptoms were developmental retardation, convulsion, strabismus, and hypoglycemia, which is rarely reported in CDG-IIg."
The case report lists developmental retardation among the main symptoms of a genetically diagnosed COG1-CDG/CDG-IIg patient.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33960418 SUPPORT Human Clinical
"We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing."
The review abstract explicitly reports neonatal seizures in a COG1-CDG patient.
Mild Intellectual Disability FREQUENT HP:0001256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild intellectual disability (HP:0001256). HP:0001256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0001256 | Intellectual disability, mild | Frequent (79-30%)"
Orphanet records mild intellectual disability as a frequent phenotype of COG1-CDG.
Cerebellar Vermis Hypoplasia FREQUENT HP:0001320 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar vermis hypoplasia (HP:0001320). HP:0001320 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0001320 | Cerebellar vermis hypoplasia | Frequent (79-30%)"
Orphanet records cerebellar vermis hypoplasia as a frequent phenotype of COG1-CDG.
Growth 3
Failure to Thrive FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0001508 | Failure to thrive | Frequent (79-30%)"
Orphanet records failure to thrive as a frequent phenotype of COG1-CDG.
Postnatal Growth Retardation FREQUENT HP:0008897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal growth retardation (HP:0008897). HP:0008897 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0008897 | Postnatal growth retardation | Frequent (79-30%)"
Orphanet records postnatal growth retardation as a frequent phenotype of COG1-CDG.
Rhizomelia FREQUENT HP:0008905 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rhizomelia (HP:0008905). HP:0008905 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0008905 | Rhizomelia | Frequent (79-30%)"
Orphanet records rhizomelia as a frequent phenotype of COG1-CDG.
Other 13
Pierre-Robin Sequence FREQUENT HP:0000201 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pierre-Robin sequence (HP:0000201). HP:0000201 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0000201 | Pierre-Robin sequence | Frequent (79-30%)"
Orphanet records Pierre-Robin sequence as a frequent phenotype of COG1-CDG.
Posterior Rib Gap FREQUENT HP:0030282 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Posterior rib gap (HP:0030282). HP:0030282 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0030282 | Posterior rib gap | Frequent (79-30%)"
Orphanet records posterior rib gap as a frequent phenotype of COG1-CDG.
Butterfly Vertebrae FREQUENT HP:0003316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Butterfly vertebrae (HP:0003316). HP:0003316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0003316 | Butterfly vertebrae | Frequent (79-30%)"
Orphanet records butterfly vertebrae as a frequent phenotype of COG1-CDG.
Type II Transferrin Isoform Profile FREQUENT HP:0012301 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Type II transferrin isoform profile (HP:0012301). HP:0012301 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0012301 | Type II transferrin isoform profile | Frequent (79-30%)"
Orphanet records type II transferrin isoform profile as a frequent phenotype of COG1-CDG.
Thin Upper Lip Vermilion FREQUENT HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0000219 | Thin upper lip vermilion | Frequent (79-30%)"
Orphanet records thin upper lip vermilion as a frequent phenotype of COG1-CDG.
Smooth Philtrum FREQUENT HP:0000319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Smooth philtrum (HP:0000319). HP:0000319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0000319 | Smooth philtrum | Frequent (79-30%)"
Orphanet records smooth philtrum as a frequent phenotype of COG1-CDG.
Posteriorly Rotated Ears FREQUENT HP:0000358 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Posteriorly rotated ears (HP:0000358). HP:0000358 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0000358 | Posteriorly rotated ears | Frequent (79-30%)"
Orphanet records posteriorly rotated ears as a frequent phenotype of COG1-CDG.
Rib Fusion FREQUENT HP:0000902 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rib fusion (HP:0000902). HP:0000902 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0000902 | Rib fusion | Frequent (79-30%)"
Orphanet records rib fusion as a frequent phenotype of COG1-CDG.
Abnormal Macular Morphology FREQUENT HP:0001103 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal macular morphology (HP:0001103). HP:0001103 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0001103 | Abnormal macular morphology | Frequent (79-30%)"
Orphanet records abnormal macular morphology as a frequent phenotype of COG1-CDG.
Enlarged Cisterna Magna FREQUENT HP:0002280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enlarged cisterna magna (HP:0002280). HP:0002280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0002280 | Enlarged cisterna magna | Frequent (79-30%)"
Orphanet records enlarged cisterna magna as a frequent phenotype of COG1-CDG.
Short Long Bone FREQUENT HP:0003026 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short long bone (HP:0003026). HP:0003026 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0003026 | Short long bone | Frequent (79-30%)"
Orphanet records short long bone as a frequent phenotype of COG1-CDG.
Irregularity of Vertebral Bodies FREQUENT HP:0004582 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Irregularity of vertebral bodies (HP:0004582). HP:0004582 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0004582 | Irregularity of vertebral bodies | Frequent (79-30%)"
Orphanet records irregular vertebral bodies as a frequent phenotype of COG1-CDG.
Atrial Septal Dilatation FREQUENT HP:0011995 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal dilatation (HP:0011995). HP:0011995 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:263508 SUPPORT Other
"HP:0011995 | Atrial septal dilatation | Frequent (79-30%)"
Orphanet records atrial septal dilatation as a frequent phenotype of COG1-CDG.
🧬

Genetic Associations

1
COG1 biallelic pathogenic variants (Loss of function mutation)
Gene: COG1 hgnc:6545 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COG1 (hgnc:6545). hgnc:6545 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive inheritance
Show evidence (3 references)
PMID:16537452 SUPPORT Human Clinical
"Sequence analysis of the COG1 cDNA and gene identified a homozygous insertion of a single nucleotide (2659–2660insC), which is predicted to lead to a premature translation stop and truncation of the C terminus of the Cog1 protein by 80 amino acids."
The discovery report identifies a homozygous truncating COG1 variant in the affected patient.
PMID:33960418 SUPPORT Human Clinical
"Exome sequencing identified a homozygous COG1 variant"
The review reports an additional homozygous frameshift COG1 variant in a COG1-CDG patient.
PMID:34625039 SUPPORT Human Clinical
"The c.2492G > A (p. Arg831Gln) mutation in exon 10 of the COG1 gene may be a potential pathogenetic variant for CDG-IIg."
The report suggests pathogenicity for the missense allele, but the abstract's wording remains cautious, so this is classified as partial support.
💊

Medical Actions

3
Symptomatic Supportive Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No disease-modifying treatment is established for COG1-CDG; care is supportive and directed to manifestations such as hypoglycemia and seizures.
Target Phenotypes: Hypoglycemia HP:0001943 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypoglycemia (HP:0001943). HP:0001943 is a phenotype from the Human Phenotype Ontology. Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34625039 SUPPORT Human Clinical
"symptomatic treatment is widely used in the clinic"
The full-text review states that COG1-CDG management is symptomatic.
Physical Therapy and Rehabilitation
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Rehabilitation can be used to support function and address impaired growth and development.
Target Phenotypes: Postnatal growth retardation HP:0008897 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Postnatal growth retardation (HP:0008897). HP:0008897 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34625039 SUPPORT Human Clinical
"body rehabilitation was also applied for the improvement of growth retardation due to the hereditary nature of this disease."
The reported patient received rehabilitation directed at growth retardation.
Glucose infusion for acute hypoglycemia
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
A reported patient recovered from hypoglycemia after glucose infusion.
Target Phenotypes: Hypoglycemia HP:0001943 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypoglycemia (HP:0001943). HP:0001943 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34625039 SUPPORT Human Clinical
"We treated the patient with glucose infusion and he was recovered from hypoglycemia."
The case report directly supports acute glucose infusion for hypoglycemia.
🔬

Biochemical Markers

2
Type II serum transferrin isoelectric focusing pattern (ABNORMAL)
Context: COG1-CDG shows a type 2 serum transferrin isoelectrofocusing pattern, consistent with abnormal Golgi-stage glycan processing.
Pathograph Readouts
Readout Of Abnormal serum N- and O-glycan processing Present Absent Diagnostic
A type II transferrin pattern reports abnormal Golgi-stage glycan processing, especially altered serum glycoprotein sialylation.
Show evidence (1 reference)
PMID:33960418 SUPPORT Human Clinical
"We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing."
The type 2 transferrin pattern is the diagnostic biochemical readout.
Show evidence (1 reference)
PMID:33960418 SUPPORT Human Clinical
"We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing."
The review abstract directly supports the type 2 transferrin biochemical pattern.
Artifact: image-1.png
image-1.png
Combined N- and O-glycosylation defect (ABNORMAL)
Context: The original COG1-CDG report described abnormalities in both N-linked and O-linked glycosylation.
Pathograph Readouts
Readout Of Defective N- and O-glycosylation Positive Diagnostic
Combined N- and O-glycosylation abnormalities report the Golgi processing defect caused by COG1-complex dysfunction.
Show evidence (1 reference)
PMID:16537452 SUPPORT Human Clinical
"This patient has a defect in both N- and O-glycosylation."
The combined abnormality directly reads out defective N- and O-glycosylation.
Show evidence (1 reference)
PMID:16537452 SUPPORT Human Clinical
"This patient has a defect in both N- and O-glycosylation."
The abstract directly states that the patient had combined N- and O-glycosylation defects.
🔬

Diagnosis

1
Transferrin isoelectric focusing with confirmatory COG1 sequencing
Diagnostic evaluation can identify a type II serum transferrin pattern and confirm COG1-CDG through molecular testing for biallelic COG1 variants.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Results: Type 2 serum transferrin isoelectrofocusing and pathogenic COG1 variants.
Show evidence (2 references)
PMID:33960418 SUPPORT Human Clinical
"We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing."
The review abstract supports the biochemical diagnostic pattern.
PMID:33960418 SUPPORT Human Clinical
"Exome sequencing identified a homozygous COG1 variant"
The abstract supports confirmatory molecular diagnosis by exome sequencing.
📈

Progression

1
Congenital to infantile multisystem presentation
Reported disease begins in the neonatal or infantile period with neurodevelopmental, hepatic, feeding, seizure, and biochemical glycosylation manifestations; long-term prognosis is hard to generalize because so few patients are known.
Show evidence (1 reference)
PMID:33960418 SUPPORT Human Clinical
"We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing."
This supports neonatal-onset multisystem disease with neurological, hepatic, dysmorphic, and biochemical manifestations.
📊

Prevalence

1
Reported COG1-CDG literature
COG1-CDG is ultra-rare; a 2021 review reported five published patients at that time.
Show evidence (1 reference)
PMID:33960418 SUPPORT Human Clinical
"COG1‐CDG has been reported in five patients."
The review provides a literature-based case count, supporting ultra-rare prevalence rather than a population incidence estimate.
{ }

Source YAML

click to show 
name: COG1-congenital disorder of glycosylation
creation_date: "2026-05-14T18:24:41Z"
description: >-
  COG1-congenital disorder of glycosylation is an extremely rare autosomal
  recessive congenital disorder of glycosylation type II caused by biallelic
  COG1 variants. COG1 deficiency disrupts the conserved oligomeric Golgi
  complex, impairs intra-Golgi trafficking and glycosylation-enzyme
  localization, and causes a multisystem neurodevelopmental syndrome with
  abnormal N- and O-glycosylation.
category: Mendelian
disease_term:
  preferred_term: COG1-congenital disorder of glycosylation
  term:
    id: MONDO:0012637
    label: COG1-congenital disorder of glycosylation
parents:
- congenital disorder of glycosylation type II
- developmental anomaly of metabolic origin
- defect in conserved oligomeric Golgi complex
synonyms:
- COG1-CDG
- CDG-IIg
- CDG2G
- congenital disorder of glycosylation type IIg
- COG1 deficiency
- conserved oligomeric Golgi complex subunit 1 deficiency
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Reported COG1-CDG patients have biallelic COG1 variants, including
    homozygous frameshift variants and compound heterozygous splice/missense
    variants.
  evidence:
  - reference: PMID:16537452
    reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of the COG1 cDNA and gene identified a homozygous
      insertion of a single nucleotide (2659–2660insC), which is predicted to
      lead to a premature translation stop and truncation of the C terminus of
      the Cog1 protein by 80 amino acids.
    explanation: >-
      The discovery report identifies a homozygous truncating COG1 variant in
      the affected patient.
  - reference: PMID:34625039
    reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic analysis showed that the patient carried the heterozygous intron
      mutation c.1070 + 3A > G (splicing) in the coding region of the COG1 gene
      that was inherited from the mother, and the heterozygous mutation
      c.2492G > A (p. Arg831Gln) in exon 10 of the COG1 gene that was inherited
      from the father.
    explanation: >-
      This case report supports biallelic COG1 involvement through compound
      heterozygous inherited variants.
prevalence:
- population: Reported COG1-CDG literature
  notes: >-
    COG1-CDG is ultra-rare; a 2021 review reported five published patients at
    that time.
  evidence:
  - reference: PMID:33960418
    reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      COG1‐CDG has been reported in five patients.
    explanation: >-
      The review provides a literature-based case count, supporting ultra-rare
      prevalence rather than a population incidence estimate.
progression:
- phase: Congenital to infantile multisystem presentation
  notes: >-
    Reported disease begins in the neonatal or infantile period with
    neurodevelopmental, hepatic, feeding, seizure, and biochemical
    glycosylation manifestations; long-term prognosis is hard to generalize
    because so few patients are known.
  evidence:
  - reference: PMID:33960418
    reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a male with neonatal seizures, dysmorphism, hepatitis and a
      type 2 serum transferrin isoelectrofocusing.
    explanation: >-
      This supports neonatal-onset multisystem disease with neurological,
      hepatic, dysmorphic, and biochemical manifestations.
pathophysiology:
- name: COG1 Deficiency Disrupts the Conserved Oligomeric Golgi Complex
  conforms_to: "congenital_disorder_of_glycosylation#Golgi N-Glycan Processing and Trafficking Defect"
  description: >-
    Pathogenic COG1 variants impair function of the conserved oligomeric Golgi
    complex, disrupting intra-Golgi trafficking and the localization or
    stability of Golgi glycosylation enzymes.
  genes:
  - preferred_term: COG1
    term:
      id: hgnc:6545
      label: COG1
  biological_processes:
  - preferred_term: Golgi vesicle transport
    modifier: ABNORMAL
    term:
      id: GO:0048193
      label: Golgi vesicle transport
  - preferred_term: intra-Golgi vesicle-mediated transport
    modifier: ABNORMAL
    term:
      id: GO:0006891
      label: intra-Golgi vesicle-mediated transport
  locations:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  evidence:
  - reference: PMID:16537452
    reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This mutation destabilizes several other COG subunits and alters their
      subcellular localization and hence the overall integrity of the COG
      complex.
    explanation: >-
      Patient-derived molecular evidence directly links the COG1 truncating
      variant to COG-complex instability and altered subcellular localization.
  downstream:
  - target: Retrograde Golgi trafficking delay
    description: >-
      COG1 splice or truncating defects can delay retrograde trafficking in
      patient fibroblasts.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19008299
      reference_title: "Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        A delay in retrograde trafficking could be demonstrated by Brefeldin A treatment of this patient's fibroblasts.
      explanation: >-
        Patient fibroblast testing directly supports a retrograde trafficking
        delay downstream of COG1 deficiency.
  - target: Defective N- and O-glycosylation
    description: >-
      COG-complex disruption alters Golgi glycosylation-enzyme localization,
      causing combined N- and O-glycosylation defects.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16537452
      reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This results in reduced levels and/or altered Golgi localization of
        α-mannosidase II and β-1,4 galactosyltransferase I, which links
        it to the glycosylation deficiency.
      explanation: >-
        The discovery paper explicitly connects altered Golgi enzyme levels or
        localization with the downstream glycosylation deficiency.
- name: Retrograde Golgi trafficking delay
  description: >-
    COG1 deficiency impairs retrograde vesicular trafficking through the Golgi,
    disrupting the trafficking environment needed to maintain glycosylation
    enzyme localization and glycan processing.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: Golgi vesicle transport
    modifier: ABNORMAL
    term:
      id: GO:0048193
      label: Golgi vesicle transport
  - preferred_term: intra-Golgi vesicle-mediated transport
    modifier: ABNORMAL
    term:
      id: GO:0006891
      label: intra-Golgi vesicle-mediated transport
  locations:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  evidence:
  - reference: PMID:19008299
    reference_title: "Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This hetero-octameric protein complex is involved in retrograde vesicular trafficking and glycosylation.
    explanation: >-
      The COG1 cerebrocostomandibular-like syndrome report places the COG
      complex in retrograde trafficking and glycosylation.
  - reference: PMID:19008299
    reference_title: "Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A delay in retrograde trafficking could be demonstrated by Brefeldin A treatment of this patient's fibroblasts.
    explanation: >-
      Brefeldin A testing demonstrates delayed retrograde trafficking in
      patient fibroblasts.
  downstream:
  - target: Defective N- and O-glycosylation
    description: >-
      Retrograde trafficking abnormalities impair maintenance of Golgi
      glycosylation machinery, producing the combined glycosylation defect.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered Golgi glycosylation-enzyme localization
    evidence:
    - reference: PMID:16537452
      reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This results in reduced levels and/or altered Golgi localization of
        α-mannosidase II and β-1,4 galactosyltransferase I, which links
        it to the glycosylation deficiency.
      explanation: >-
        The discovery paper identifies altered localization of Golgi
        glycosylation enzymes as the bridge to the glycosylation defect.
- name: Defective N- and O-glycosylation
  conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
  description: >-
    Disrupted Golgi trafficking impairs glycoprotein processing, producing a
    type II CDG pattern with combined N-linked and O-linked glycosylation
    abnormalities.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  - preferred_term: protein O-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006493
      label: protein O-linked glycosylation
  chemical_entities:
  - preferred_term: N-glycan
    modifier: ABNORMAL
    term:
      id: CHEBI:59520
      label: N-glycan
  - preferred_term: O-glycan
    modifier: ABNORMAL
    term:
      id: CHEBI:59521
      label: O-glycan
  evidence:
  - reference: PMID:16537452
    reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This patient has a defect in both N- and O-glycosylation.
    explanation: >-
      The abstract directly states the combined N- and O-glycosylation defect
      in the COG1-CDG patient.
  - reference: PMID:16537452
    reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mass spectrometric analysis of the structures of the N-linked glycans
      released from glycoproteins from the patient's serum revealed a reduction
      in sialic acid and galactose residues.
    explanation: >-
      Serum glycan mass spectrometry supports abnormal N-glycan processing in
      the affected patient.
  - reference: PMID:16537452
    reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Peanut agglutinin (PNA) lectin staining revealed a decrease in sialic
      acids on core 1 mucin type O-glycans, indicating a combined defect in
      N- and O-glycosylation.
    explanation: >-
      PNA lectin staining supports the O-glycosylation component of the
      combined glycosylation defect.
  downstream:
  - target: Abnormal serum N- and O-glycan processing
    description: >-
      Combined glycosylation impairment produces abnormal serum N-glycan
      sialylation/galactosylation and abnormal mucin-type O-glycan sialylation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16537452
      reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mass spectrometric analysis of the structures of the N-linked glycans
        released from glycoproteins from the patient's serum revealed a reduction
        in sialic acid and galactose residues.
      explanation: >-
        Patient serum mass spectrometry directly supports abnormal N-glycan
        processing.
  - target: Type II Transferrin Isoform Profile
    description: >-
      Defective Golgi glycosylation can be detected clinically as a type II
      transferrin isoform profile.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33960418
      reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a male with neonatal seizures, dysmorphism, hepatitis and a
        type 2 serum transferrin isoelectrofocusing.
      explanation: >-
        The reported type 2 transferrin isoelectrofocusing pattern provides a
        direct biochemical readout of abnormal Golgi-stage glycosylation.
  - target: Failure to Thrive
    description: >-
      Orphanet records failure to thrive as part of the multisystem COG1-CDG
      phenotype spectrum.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001508 | Failure to thrive | Frequent (79-30%)"
      explanation: Orphanet records failure to thrive as a frequent COG1-CDG phenotype.
  - target: Neurological involvement
    description: >-
      COG1-CDG glycosylation defects are associated with developmental delay
      and seizures or convulsions in reported patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34625039
      reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient was male, and the main clinical symptoms were developmental
        retardation, convulsion, strabismus, and hypoglycemia, which is rarely
        reported in CDG-IIg.
      explanation: >-
        This COG1-CDG case report supports neurological manifestations through
        developmental retardation and convulsion.
  - target: Craniofacial dysmorphism involvement
    description: >-
      COG1-CDG glycosylation defects are associated with dysmorphism in a
      reported neonatal presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33960418
      reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a male with neonatal seizures, dysmorphism, hepatitis and a
        type 2 serum transferrin isoelectrofocusing.
      explanation: >-
        The review abstract supports craniofacial involvement through
        dysmorphism in a reported patient.
  - target: Ocular alignment involvement
    description: >-
      COG1-CDG glycosylation defects are associated with strabismus in a
      reported compound heterozygous case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34625039
      reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient was male, and the main clinical symptoms were developmental
        retardation, convulsion, strabismus, and hypoglycemia, which is rarely
        reported in CDG-IIg.
      explanation: >-
        This case report supports ocular alignment involvement through
        strabismus.
  - target: Hepatic involvement
    description: >-
      Reported patients can show hepatitis as a hepatic manifestation of
      COG1-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33960418
      reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a male with neonatal seizures, dysmorphism, hepatitis and a
        type 2 serum transferrin isoelectrofocusing.
      explanation: >-
        The review abstract supports hepatic involvement through hepatitis in a
        reported patient.
  - target: Hypoglycemia susceptibility
    description: >-
      Reported patients can show hypoglycemia as a metabolic manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34625039
      reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient was male, and the main clinical symptoms were developmental
        retardation, convulsion, strabismus, and hypoglycemia, which is rarely
        reported in CDG-IIg.
      explanation: >-
        This case report supports hypoglycemia as a metabolic manifestation.
  - target: Costovertebral skeletal involvement
    description: >-
      A COG1 splice-variant presentation included costovertebral dysplasia as a
      skeletal manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19008299
      reference_title: "Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The costovertebral dysplasia of the two patients has been described in
        cerebrocostomandibular syndrome (CCMS), but also in
        cerebrofaciothoracic dysplasia and spondylocostal dysostosis.
      explanation: >-
        The abstract supports costovertebral skeletal involvement in two
        COG1-mutated patients.
  - target: Abnormal Macular Morphology
    description: Orphanet records abnormal macular morphology as a frequent manifestation of COG1-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001103 | Abnormal macular morphology | Frequent (79-30%)"
      explanation: Orphanet supports this distal phenotype in the COG1-CDG spectrum.
  - target: Pulmonary Arterial Hypertension
    description: Orphanet records pulmonary arterial hypertension as a frequent manifestation of COG1-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002092 | Pulmonary arterial hypertension | Frequent (79-30%)"
      explanation: Orphanet supports this distal phenotype in the COG1-CDG spectrum.
  - target: Postnatal Growth Retardation
    description: Orphanet records postnatal growth retardation as a frequent manifestation of COG1-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0008897 | Postnatal growth retardation | Frequent (79-30%)"
      explanation: Orphanet supports this distal phenotype in the COG1-CDG spectrum.
  - target: Atrial Septal Dilatation
    description: Orphanet records atrial septal dilatation as a frequent manifestation of COG1-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0011995 | Atrial septal dilatation | Frequent (79-30%)"
      explanation: Orphanet supports this distal phenotype in the COG1-CDG spectrum.

- name: Abnormal serum N- and O-glycan processing
  description: >-
    Patient serum and lectin assays show reduced sialic acid and galactose on
    N-glycans and reduced sialylation of core 1 mucin-type O-glycans, producing
    the type II CDG biochemical signature.
  chemical_entities:
  - preferred_term: N-glycan
    modifier: ABNORMAL
    term:
      id: CHEBI:59520
      label: N-glycan
  - preferred_term: O-glycan
    modifier: ABNORMAL
    term:
      id: CHEBI:59521
      label: O-glycan
  evidence:
  - reference: PMID:16537452
    reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mass spectrometric analysis of the structures of the N-linked glycans
      released from glycoproteins from the patient's serum revealed a reduction
      in sialic acid and galactose residues.
    explanation: >-
      This directly supports abnormal serum N-glycan processing.
  - reference: PMID:16537452
    reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Peanut agglutinin (PNA) lectin staining revealed a decrease in sialic
      acids on core 1 mucin type O-glycans, indicating a combined defect in
      N- and O-glycosylation.
    explanation: >-
      This directly supports abnormal mucin-type O-glycan sialylation.
- name: Neurological involvement
  description: >-
    The reported COG1-CDG neurological spectrum includes developmental delay
    and neonatal seizures or convulsions.
  evidence:
  - reference: PMID:34625039
    reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was male, and the main clinical symptoms were developmental
      retardation, convulsion, strabismus, and hypoglycemia, which is rarely
      reported in CDG-IIg.
    explanation: >-
      This COG1-CDG case report supports developmental delay and convulsions.
  - reference: PMID:33960418
    reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a male with neonatal seizures, dysmorphism, hepatitis and a
      type 2 serum transferrin isoelectrofocusing.
    explanation: >-
      The review abstract supports neonatal seizures in a reported patient.
  downstream:
  - target: Global developmental delay
    description: >-
      Developmental retardation is one of the main reported clinical symptoms.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34625039
      reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient was male, and the main clinical symptoms were developmental
        retardation, convulsion, strabismus, and hypoglycemia, which is rarely
        reported in CDG-IIg.
      explanation: >-
        This directly supports developmental retardation in COG1-CDG.
  - target: Seizures
    description: >-
      Seizures or convulsions are reported neurologic manifestations.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33960418
      reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a male with neonatal seizures, dysmorphism, hepatitis and a
        type 2 serum transferrin isoelectrofocusing.
      explanation: >-
        This directly supports neonatal seizures in COG1-CDG.
  - target: Mild Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001256 | Intellectual disability, mild | Frequent (79-30%)"
      explanation: Orphanet supports mild intellectual disability in the COG1-CDG spectrum.
  - target: Cerebellar Vermis Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001320 | Cerebellar vermis hypoplasia | Frequent (79-30%)"
      explanation: Orphanet supports cerebellar vermis hypoplasia in the COG1-CDG spectrum.
  - target: Enlarged Cisterna Magna
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002280 | Enlarged cisterna magna | Frequent (79-30%)"
      explanation: Orphanet supports enlarged cisterna magna in the COG1-CDG spectrum.
- name: Craniofacial dysmorphism involvement
  description: >-
    Dysmorphism is reported as a craniofacial manifestation in COG1-CDG.
  evidence:
  - reference: PMID:33960418
    reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a male with neonatal seizures, dysmorphism, hepatitis and a
      type 2 serum transferrin isoelectrofocusing.
    explanation: >-
      The review abstract supports dysmorphism in a reported COG1-CDG patient.
  downstream:
  - target: Dysmorphism
    description: >-
      Dysmorphism is reported in the neonatal COG1-CDG presentation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33960418
      reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a male with neonatal seizures, dysmorphism, hepatitis and a
        type 2 serum transferrin isoelectrofocusing.
      explanation: >-
        This directly supports dysmorphism in COG1-CDG.
  - target: Pierre-Robin Sequence
    description: >-
      Orphanet records Pierre-Robin sequence as a frequent craniofacial
      phenotype of COG1-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000201 | Pierre-Robin sequence | Frequent (79-30%)"
      explanation: Orphanet records Pierre-Robin sequence as a frequent COG1-CDG phenotype.
  - target: Thin Upper Lip Vermilion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000219 | Thin upper lip vermilion | Frequent (79-30%)"
      explanation: Orphanet supports thin upper lip vermilion in the COG1-CDG spectrum.
  - target: Smooth Philtrum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000319 | Smooth philtrum | Frequent (79-30%)"
      explanation: Orphanet supports smooth philtrum in the COG1-CDG spectrum.
  - target: Posteriorly Rotated Ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000358 | Posteriorly rotated ears | Frequent (79-30%)"
      explanation: Orphanet supports posteriorly rotated ears in the COG1-CDG spectrum.
  - target: Short Neck
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000470 | Short neck | Frequent (79-30%)"
      explanation: Orphanet supports short neck in the COG1-CDG spectrum.
- name: Ocular alignment involvement
  description: >-
    Strabismus is reported as an ocular alignment manifestation in COG1-CDG.
  evidence:
  - reference: PMID:34625039
    reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was male, and the main clinical symptoms were developmental
      retardation, convulsion, strabismus, and hypoglycemia, which is rarely
      reported in CDG-IIg.
    explanation: >-
      The case report supports strabismus in COG1-CDG/CDG-IIg.
  downstream:
  - target: Strabismus
    description: >-
      Strabismus is reported among the main symptoms in a COG1-CDG case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34625039
      reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient was male, and the main clinical symptoms were developmental
        retardation, convulsion, strabismus, and hypoglycemia, which is rarely
        reported in CDG-IIg.
      explanation: >-
        This directly supports strabismus in the reported patient.
- name: Hepatic involvement
  description: >-
    COG1-CDG can include hepatitis alongside the type II glycosylation defect.
  evidence:
  - reference: PMID:33960418
    reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a male with neonatal seizures, dysmorphism, hepatitis and a
      type 2 serum transferrin isoelectrofocusing.
    explanation: >-
      This supports hepatitis in a reported COG1-CDG patient.
  downstream:
  - target: Hepatitis
    description: >-
      Hepatitis is a reported hepatic manifestation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33960418
      reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a male with neonatal seizures, dysmorphism, hepatitis and a
        type 2 serum transferrin isoelectrofocusing.
      explanation: >-
        This directly supports hepatitis in COG1-CDG.
- name: Hypoglycemia susceptibility
  description: >-
    COG1-CDG can include hypoglycemia alongside the type II glycosylation
    defect.
  evidence:
  - reference: PMID:34625039
    reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was male, and the main clinical symptoms were developmental
      retardation, convulsion, strabismus, and hypoglycemia, which is rarely
      reported in CDG-IIg.
    explanation: >-
      This supports hypoglycemia in a reported COG1-CDG patient.
  downstream:
  - target: Hypoglycemia
    description: >-
      Hypoglycemia is reported as a main symptom and was responsive to glucose
      infusion in one case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34625039
      reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient was male, and the main clinical symptoms were developmental
        retardation, convulsion, strabismus, and hypoglycemia, which is rarely
        reported in CDG-IIg.
      explanation: >-
        This directly supports hypoglycemia in COG1-CDG.
- name: Costovertebral skeletal involvement
  description: >-
    Two COG1-mutated patients with the recurrent c.1070+5G>A splice variant
    were described with cerebrocostomandibular-like syndrome and costovertebral
    dysplasia, supporting a skeletal branch in this mutation class.
  evidence:
  - reference: PMID:19008299
    reference_title: "Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe two patients with a cerebrocostomandibular-like syndrome and
      a novel mutation in conserved oligomeric Golgi (COG) subunit 1
    explanation: >-
      The abstract supports a cerebrocostomandibular-like skeletal presentation
      in COG1-mutated patients.
  - reference: PMID:19008299
    reference_title: "Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The costovertebral dysplasia of the two patients has been described in
      cerebrocostomandibular syndrome (CCMS), but also in
      cerebrofaciothoracic dysplasia and spondylocostal dysostosis.
    explanation: >-
      The abstract directly supports costovertebral dysplasia in the two
      reported COG1-mutated patients.
  - reference: PMID:19008299
    reference_title: "Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified in both patients an intronic mutation, c.1070+5G>A, that
      disrupts a splice donor site and leads to skipping of exon 6, a frameshift
      and a premature stopcodon in exon 7.
    explanation: >-
      This identifies the splice-variant class associated with the two
      costovertebral dysplasia patients.
  downstream:
  - target: Costovertebral dysplasia
    description: >-
      Costovertebral dysplasia is the reported skeletal manifestation in the two
      COG1 c.1070+5G>A patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19008299
      reference_title: "Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The costovertebral dysplasia of the two patients has been described in
        cerebrocostomandibular syndrome (CCMS), but also in
        cerebrofaciothoracic dysplasia and spondylocostal dysostosis.
      explanation: >-
        The abstract directly supports costovertebral dysplasia as a skeletal
        phenotype.
  - target: Posterior Rib Gap
    description: >-
      Orphanet records posterior rib gap as a frequent skeletal phenotype of
      COG1-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0030282 | Posterior rib gap | Frequent (79-30%)"
      explanation: Orphanet records posterior rib gap as a frequent COG1-CDG phenotype.
  - target: Butterfly Vertebrae
    description: >-
      Orphanet records butterfly vertebrae as a frequent vertebral phenotype of
      COG1-CDG.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003316 | Butterfly vertebrae | Frequent (79-30%)"
      explanation: Orphanet records butterfly vertebrae as a frequent COG1-CDG phenotype.
  - target: Rib Fusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000902 | Rib fusion | Frequent (79-30%)"
      explanation: Orphanet supports rib fusion in the COG1-CDG spectrum.
  - target: Irregularity of Vertebral Bodies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0004582 | Irregularity of vertebral bodies | Frequent (79-30%)"
      explanation: Orphanet supports irregular vertebral bodies in the COG1-CDG spectrum.
  - target: Short Long Bone
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003026 | Short long bone | Frequent (79-30%)"
      explanation: Orphanet supports short long bone in the COG1-CDG spectrum.
  - target: Rhizomelia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0008905 | Rhizomelia | Frequent (79-30%)"
      explanation: Orphanet supports rhizomelia in the COG1-CDG spectrum.
  - target: Osteopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000938 | Osteopenia | Frequent (79-30%)"
      explanation: Orphanet supports osteopenia in the COG1-CDG spectrum.
  - target: Talipes Equinovarus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:263508
      reference_title: "COG1-CDG"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001762 | Talipes equinovarus | Frequent (79-30%)"
      explanation: Orphanet supports talipes equinovarus in the COG1-CDG spectrum.
phenotypes:
- category: Neurological
  name: Global developmental delay
  description: >-
    Developmental delay is part of the reported COG1-CDG neurological
    phenotype.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:34625039
    reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was male, and the main clinical symptoms were developmental
      retardation, convulsion, strabismus, and hypoglycemia, which is rarely
      reported in CDG-IIg.
    explanation: >-
      The case report lists developmental retardation among the main symptoms
      of a genetically diagnosed COG1-CDG/CDG-IIg patient.
- category: Neurological
  name: Seizures
  description: >-
    Seizures, including neonatal seizures in one review case and convulsions in
    another case report, are reported neurological manifestations.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33960418
    reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a male with neonatal seizures, dysmorphism, hepatitis and a
      type 2 serum transferrin isoelectrofocusing.
    explanation: >-
      The review abstract explicitly reports neonatal seizures in a COG1-CDG
      patient.
- category: Craniofacial
  name: Dysmorphism
  description: >-
    Dysmorphic features are reported as part of the neonatal COG1-CDG
    presentation.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:33960418
    reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a male with neonatal seizures, dysmorphism, hepatitis and a
      type 2 serum transferrin isoelectrofocusing.
    explanation: >-
      The review abstract explicitly reports dysmorphism in a COG1-CDG patient;
      the HPO term is a broad mapping for facial dysmorphism.
- category: Musculoskeletal
  name: Costovertebral dysplasia
  description: >-
    Costovertebral dysplasia was reported in two COG1 c.1070+5G>A patients with
    a cerebrocostomandibular-like presentation, suggesting a skeletal phenotype
    in this mutation class.
  phenotype_term:
    preferred_term: Costovertebral dysplasia
    term:
      id: HP:0000925
      label: Abnormality of the vertebral column
  evidence:
  - reference: PMID:19008299
    reference_title: "Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The costovertebral dysplasia of the two patients has been described in
      cerebrocostomandibular syndrome (CCMS), but also in
      cerebrofaciothoracic dysplasia and spondylocostal dysostosis.
    explanation: >-
      The abstract directly supports costovertebral dysplasia; HP:0000925 is a
      broad mapping for the vertebral component of the skeletal phenotype.
  - reference: PMID:19008299
    reference_title: "Cerebrocostomandibular-like syndrome and a mutation in the conserved oligomeric Golgi complex, subunit 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified in both patients an intronic mutation, c.1070+5G>A, that
      disrupts a splice donor site and leads to skipping of exon 6, a frameshift
      and a premature stopcodon in exon 7.
    explanation: >-
      This identifies the splice-variant class associated with the two
      costovertebral dysplasia patients.
- category: Craniofacial
  name: Pierre-Robin Sequence
  frequency: FREQUENT
  description: >
    Pierre-Robin sequence is recorded as a frequent craniofacial phenotype of
    COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Pierre-Robin sequence
    term:
      id: HP:0000201
      label: Pierre-Robin sequence
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000201 | Pierre-Robin sequence | Frequent (79-30%)"
    explanation: Orphanet records Pierre-Robin sequence as a frequent phenotype of COG1-CDG.
- category: Growth
  name: Failure to Thrive
  frequency: FREQUENT
  description: >
    Failure to thrive is recorded as a frequent phenotype of COG1-CDG in
    Orphanet.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001508 | Failure to thrive | Frequent (79-30%)"
    explanation: Orphanet records failure to thrive as a frequent phenotype of COG1-CDG.
- category: Musculoskeletal
  name: Posterior Rib Gap
  frequency: FREQUENT
  description: >
    Posterior rib gap is recorded as a frequent skeletal phenotype of COG1-CDG
    in Orphanet.
  phenotype_term:
    preferred_term: Posterior rib gap
    term:
      id: HP:0030282
      label: Posterior rib gap
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030282 | Posterior rib gap | Frequent (79-30%)"
    explanation: Orphanet records posterior rib gap as a frequent phenotype of COG1-CDG.
- category: Musculoskeletal
  name: Butterfly Vertebrae
  frequency: FREQUENT
  description: >
    Butterfly vertebrae are recorded as a frequent vertebral phenotype of
    COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Butterfly vertebrae
    term:
      id: HP:0003316
      label: Butterfly vertebrae
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003316 | Butterfly vertebrae | Frequent (79-30%)"
    explanation: Orphanet records butterfly vertebrae as a frequent phenotype of COG1-CDG.
- category: Biochemical
  name: Type II Transferrin Isoform Profile
  frequency: FREQUENT
  description: >
    A type II transferrin isoform profile is recorded as a frequent biochemical
    phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Type II transferrin isoform profile
    term:
      id: HP:0012301
      label: Type II transferrin isoform profile
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012301 | Type II transferrin isoform profile | Frequent (79-30%)"
    explanation: Orphanet records type II transferrin isoform profile as a frequent phenotype of COG1-CDG.
- category: Hepatic
  name: Hepatitis
  description: >-
    Hepatic involvement with hepatitis or elevated transaminases can occur in
    COG1-CDG.
  phenotype_term:
    preferred_term: Hepatitis
    term:
      id: HP:0012115
      label: Hepatitis
  evidence:
  - reference: PMID:33960418
    reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a male with neonatal seizures, dysmorphism, hepatitis and a
      type 2 serum transferrin isoelectrofocusing.
    explanation: >-
      The review abstract explicitly identifies hepatitis in a COG1-CDG
      patient.
- category: Endocrine
  name: Hypoglycemia
  description: >-
    Hypoglycemia has been reported in a COG1-CDG case and may require acute
    glucose treatment.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:34625039
    reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was male, and the main clinical symptoms were developmental
      retardation, convulsion, strabismus, and hypoglycemia, which is rarely
      reported in CDG-IIg.
    explanation: >-
      The case report explicitly lists hypoglycemia as a main symptom in
      COG1-CDG/CDG-IIg.
- category: Ophthalmologic
  name: Strabismus
  description: >-
    Strabismus was reported among the main symptoms in a compound heterozygous
    COG1-CDG case.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:34625039
    reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was male, and the main clinical symptoms were developmental
      retardation, convulsion, strabismus, and hypoglycemia, which is rarely
      reported in CDG-IIg.
    explanation: >-
      The case report directly lists strabismus in the affected patient.
- category: Craniofacial
  name: Thin Upper Lip Vermilion
  frequency: FREQUENT
  description: Thin upper lip vermilion is recorded as a frequent craniofacial phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000219 | Thin upper lip vermilion | Frequent (79-30%)"
    explanation: Orphanet records thin upper lip vermilion as a frequent phenotype of COG1-CDG.
- category: Craniofacial
  name: Smooth Philtrum
  frequency: FREQUENT
  description: Smooth philtrum is recorded as a frequent craniofacial phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Smooth philtrum
    term:
      id: HP:0000319
      label: Smooth philtrum
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000319 | Smooth philtrum | Frequent (79-30%)"
    explanation: Orphanet records smooth philtrum as a frequent phenotype of COG1-CDG.
- category: Craniofacial
  name: Posteriorly Rotated Ears
  frequency: FREQUENT
  description: Posteriorly rotated ears are recorded as a frequent craniofacial phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Posteriorly rotated ears
    term:
      id: HP:0000358
      label: Posteriorly rotated ears
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000358 | Posteriorly rotated ears | Frequent (79-30%)"
    explanation: Orphanet records posteriorly rotated ears as a frequent phenotype of COG1-CDG.
- category: Craniofacial
  name: Short Neck
  frequency: FREQUENT
  description: Short neck is recorded as a frequent craniofacial phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000470 | Short neck | Frequent (79-30%)"
    explanation: Orphanet records short neck as a frequent phenotype of COG1-CDG.
- category: Musculoskeletal
  name: Rib Fusion
  frequency: FREQUENT
  description: Rib fusion is recorded as a frequent skeletal phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Rib fusion
    term:
      id: HP:0000902
      label: Rib fusion
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000902 | Rib fusion | Frequent (79-30%)"
    explanation: Orphanet records rib fusion as a frequent phenotype of COG1-CDG.
- category: Musculoskeletal
  name: Osteopenia
  frequency: FREQUENT
  description: Osteopenia is recorded as a frequent skeletal phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000938 | Osteopenia | Frequent (79-30%)"
    explanation: Orphanet records osteopenia as a frequent phenotype of COG1-CDG.
- category: Ophthalmologic
  name: Abnormal Macular Morphology
  frequency: FREQUENT
  description: Abnormal macular morphology is recorded as a frequent ophthalmologic phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Abnormal macular morphology
    term:
      id: HP:0001103
      label: Abnormal macular morphology
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001103 | Abnormal macular morphology | Frequent (79-30%)"
    explanation: Orphanet records abnormal macular morphology as a frequent phenotype of COG1-CDG.
- category: Neurological
  name: Mild Intellectual Disability
  frequency: FREQUENT
  description: Mild intellectual disability is recorded as a frequent neurological phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001256 | Intellectual disability, mild | Frequent (79-30%)"
    explanation: Orphanet records mild intellectual disability as a frequent phenotype of COG1-CDG.
- category: Neurological
  name: Cerebellar Vermis Hypoplasia
  frequency: FREQUENT
  description: Cerebellar vermis hypoplasia is recorded as a frequent neurological phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Cerebellar vermis hypoplasia
    term:
      id: HP:0001320
      label: Cerebellar vermis hypoplasia
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001320 | Cerebellar vermis hypoplasia | Frequent (79-30%)"
    explanation: Orphanet records cerebellar vermis hypoplasia as a frequent phenotype of COG1-CDG.
- category: Musculoskeletal
  name: Talipes Equinovarus
  frequency: FREQUENT
  description: Talipes equinovarus is recorded as a frequent skeletal phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001762 | Talipes equinovarus | Frequent (79-30%)"
    explanation: Orphanet records talipes equinovarus as a frequent phenotype of COG1-CDG.
- category: Cardiopulmonary
  name: Pulmonary Arterial Hypertension
  frequency: FREQUENT
  description: Pulmonary arterial hypertension is recorded as a frequent cardiopulmonary phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002092 | Pulmonary arterial hypertension | Frequent (79-30%)"
    explanation: Orphanet records pulmonary arterial hypertension as a frequent phenotype of COG1-CDG.
- category: Neurological
  name: Enlarged Cisterna Magna
  frequency: FREQUENT
  description: Enlarged cisterna magna is recorded as a frequent neurological phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Enlarged cisterna magna
    term:
      id: HP:0002280
      label: Enlarged cisterna magna
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002280 | Enlarged cisterna magna | Frequent (79-30%)"
    explanation: Orphanet records enlarged cisterna magna as a frequent phenotype of COG1-CDG.
- category: Musculoskeletal
  name: Short Long Bone
  frequency: FREQUENT
  description: Short long bone is recorded as a frequent skeletal phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Short long bone
    term:
      id: HP:0003026
      label: Short long bone
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003026 | Short long bone | Frequent (79-30%)"
    explanation: Orphanet records short long bone as a frequent phenotype of COG1-CDG.
- category: Musculoskeletal
  name: Irregularity of Vertebral Bodies
  frequency: FREQUENT
  description: Irregularity of vertebral bodies is recorded as a frequent skeletal phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Irregularity of vertebral bodies
    term:
      id: HP:0004582
      label: Irregularity of vertebral bodies
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004582 | Irregularity of vertebral bodies | Frequent (79-30%)"
    explanation: Orphanet records irregular vertebral bodies as a frequent phenotype of COG1-CDG.
- category: Growth
  name: Postnatal Growth Retardation
  frequency: FREQUENT
  description: Postnatal growth retardation is recorded as a frequent growth phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008897 | Postnatal growth retardation | Frequent (79-30%)"
    explanation: Orphanet records postnatal growth retardation as a frequent phenotype of COG1-CDG.
- category: Musculoskeletal
  name: Rhizomelia
  frequency: FREQUENT
  description: Rhizomelia is recorded as a frequent skeletal phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Rhizomelia
    term:
      id: HP:0008905
      label: Rhizomelia
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008905 | Rhizomelia | Frequent (79-30%)"
    explanation: Orphanet records rhizomelia as a frequent phenotype of COG1-CDG.
- category: Cardiovascular
  name: Atrial Septal Dilatation
  frequency: FREQUENT
  description: Atrial septal dilatation is recorded as a frequent cardiovascular phenotype of COG1-CDG in Orphanet.
  phenotype_term:
    preferred_term: Atrial septal dilatation
    term:
      id: HP:0011995
      label: Atrial septal dilatation
  evidence:
  - reference: ORPHA:263508
    reference_title: "COG1-CDG"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011995 | Atrial septal dilatation | Frequent (79-30%)"
    explanation: Orphanet records atrial septal dilatation as a frequent phenotype of COG1-CDG.
biochemical:
- name: Type II serum transferrin isoelectric focusing pattern
  presence: ABNORMAL
  context: >-
    COG1-CDG shows a type 2 serum transferrin isoelectrofocusing pattern,
    consistent with abnormal Golgi-stage glycan processing.
  biomarker_term:
    preferred_term: N-glycan
    term:
      id: CHEBI:59520
      label: N-glycan
  readouts:
  - target: Abnormal serum N- and O-glycan processing
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A type II transferrin pattern reports abnormal Golgi-stage glycan
      processing, especially altered serum glycoprotein sialylation.
    evidence:
    - reference: PMID:33960418
      reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a male with neonatal seizures, dysmorphism, hepatitis and a
        type 2 serum transferrin isoelectrofocusing.
      explanation: The type 2 transferrin pattern is the diagnostic biochemical readout.
  evidence:
  - reference: PMID:33960418
    reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a male with neonatal seizures, dysmorphism, hepatitis and a
      type 2 serum transferrin isoelectrofocusing.
    explanation: >-
      The review abstract directly supports the type 2 transferrin biochemical
      pattern.
    images:
    - research/COG1-congenital_disorder_of_glycosylation-deep-research-falcon_artifacts/image-1.png
- name: Combined N- and O-glycosylation defect
  presence: ABNORMAL
  context: >-
    The original COG1-CDG report described abnormalities in both N-linked and
    O-linked glycosylation.
  biomarker_term:
    preferred_term: O-glycan
    term:
      id: CHEBI:59521
      label: O-glycan
  readouts:
  - target: Defective N- and O-glycosylation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Combined N- and O-glycosylation abnormalities report the Golgi processing
      defect caused by COG1-complex dysfunction.
    evidence:
    - reference: PMID:16537452
      reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This patient has a defect in both N- and O-glycosylation.
      explanation: The combined abnormality directly reads out defective N- and O-glycosylation.
  evidence:
  - reference: PMID:16537452
    reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This patient has a defect in both N- and O-glycosylation.
    explanation: >-
      The abstract directly states that the patient had combined N- and
      O-glycosylation defects.
genetic:
- name: COG1 biallelic pathogenic variants
  association: Loss of function mutation
  relationship_type: CAUSATIVE
  presence: Pathogenic
  gene_term:
    preferred_term: COG1
    term:
      id: hgnc:6545
      label: COG1
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:16537452
      reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sequence analysis of the COG1 cDNA and gene identified a homozygous
        insertion of a single nucleotide (2659–2660insC), which is predicted to
        lead to a premature translation stop and truncation of the C terminus of
        the Cog1 protein by 80 amino acids.
      explanation: A homozygous pathogenic allele supports recessive inheritance.
  features: >-
    Reported COG1-CDG alleles include truncating frameshift variants and
    splice-region variants; one reported compound heterozygous case included a
    p.Arg831Gln missense variant described as a potential pathogenetic variant.
  evidence:
  - reference: PMID:16537452
    reference_title: "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of the COG1 cDNA and gene identified a homozygous
      insertion of a single nucleotide (2659–2660insC), which is predicted to
      lead to a premature translation stop and truncation of the C terminus of
      the Cog1 protein by 80 amino acids.
    explanation: >-
      The discovery report identifies a homozygous truncating COG1 variant in
      the affected patient.
  - reference: PMID:33960418
    reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing identified a homozygous COG1 variant
    explanation: >-
      The review reports an additional homozygous frameshift COG1 variant in a
      COG1-CDG patient.
  - reference: PMID:34625039
    reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The c.2492G > A (p. Arg831Gln) mutation in exon 10 of the COG1 gene may
      be a potential pathogenetic variant for CDG-IIg.
    explanation: >-
      The report suggests pathogenicity for the missense allele, but the
      abstract's wording remains cautious, so this is classified as partial
      support.
diagnosis:
- name: Transferrin isoelectric focusing with confirmatory COG1 sequencing
  description: >-
    Diagnostic evaluation can identify a type II serum transferrin pattern and
    confirm COG1-CDG through molecular testing for biallelic COG1 variants.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: >-
    Type 2 serum transferrin isoelectrofocusing and pathogenic COG1 variants.
  evidence:
  - reference: PMID:33960418
    reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a male with neonatal seizures, dysmorphism, hepatitis and a
      type 2 serum transferrin isoelectrofocusing.
    explanation: >-
      The review abstract supports the biochemical diagnostic pattern.
  - reference: PMID:33960418
    reference_title: "COG1-congenital disorders of glycosylation: Milder presentation and review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing identified a homozygous COG1 variant
    explanation: >-
      The abstract supports confirmatory molecular diagnosis by exome
      sequencing.
treatments:
- name: Symptomatic Supportive Care
  description: >-
    No disease-modifying treatment is established for COG1-CDG; care is
    supportive and directed to manifestations such as hypoglycemia and
    seizures.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:34625039
    reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "symptomatic treatment is widely used in the clinic"
    explanation: The full-text review states that COG1-CDG management is symptomatic.
- name: Physical Therapy and Rehabilitation
  description: Rehabilitation can be used to support function and address impaired growth and development.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:34625039
    reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "body rehabilitation was also applied for the improvement of growth retardation due to the hereditary nature of this disease."
    explanation: The reported patient received rehabilitation directed at growth retardation.
- name: Glucose infusion for acute hypoglycemia
  description: >-
    A reported patient recovered from hypoglycemia after glucose infusion.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:34625039
    reference_title: "Component of oligomeric Golgi complex 1 deficiency leads to hypoglycemia: a case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We treated the patient with glucose infusion and he was recovered from
      hypoglycemia.
    explanation: >-
      The case report directly supports acute glucose infusion for hypoglycemia.
review_notes: >-
  The complete Orphanet Frequent (79-30%) phenotype band is modeled here.
  Additional occasional features, including generalized hypotonia and
  progressive microcephaly, remain available in the structured Orphanet record
  for future expansion; feeding and swallowing problems are described in the
  broader review literature but are not modeled as prevalence-qualified nodes.
📚

References & Deep Research

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 41 citations 2026-05-14T14:50:32.873379

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: COG1-congenital disorder of glycosylation
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on COG1-congenital disorder of glycosylation covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Disease Characteristics Report: COG1‑congenital disorder of glycosylation (COG1‑CDG / CDG‑IIg)

Target disease: COG1‑congenital disorder of glycosylation (COG1‑CDG), historically CDG‑IIg. (j2009cdgnomenclaturetime pages 3-4, wolfe2013congenitaldisordersof pages 3-5)

Evidence base note: The COG1‑CDG literature remains dominated by a small number of individual case reports/series and narrative reviews (not EHR‑scale datasets), so most disease characteristics below are derived from individual patients and aggregated review tables rather than population studies. (foulquier2006conservedoligomericgolgi pages 2-3, salazar2021cog1‐congenitaldisordersof pages 1-3, huang2021componentofoligomeric pages 3-6)

1. Disease information

1.1 Concise overview (definition)

COG1‑CDG is a Mendelian (autosomal recessive) congenital disorder of glycosylation caused by biallelic pathogenic variants in COG1, encoding a subunit of the conserved oligomeric Golgi (COG) complex, which is required for intra‑Golgi trafficking and maintenance of Golgi glycosylation machinery. (salazar2021cog1‐congenitaldisordersof pages 1-3, foulquier2006conservedoligomericgolgi pages 2-3, reynders2011howgolgiglycosylation pages 6-7)

The discovery report proposed the name “CDG‑II Cog1” (“CDG‑II caused by Cog1 deficiency”). (foulquier2006conservedoligomericgolgi pages 1-2)

1.2 Key identifiers (OMIM/Orphanet/ICD/MeSH/MONDO)

The retrieved literature contains inconsistent OMIM numbering across secondary sources and did not include Orphanet/ICD/MeSH/MONDO identifiers in extracted text:

Identifier type ID/value Label/name used Source (paper, year) URL / DOI Notes / ambiguities
OMIM (reported in nomenclature table) 606973 COG1-CDG (CDG-IIg); defective protein: Component of conserved oligomeric Golgi complex 1 Jaeken et al., 2009 (j2009cdgnomenclaturetime pages 3-4) https://doi.org/10.1016/j.bbadis.2009.08.005 Reported in a CDG nomenclature table; excerpt does not provide Orphanet, MONDO, or ICD identifiers.
OMIM (reported in review table) 611209 COG1 deficiency; COG1-CDG (CDG-IIg) Wolfe & Krasnewich, 2013 (wolfe2013congenitaldisordersof pages 3-5) https://doi.org/10.1002/ddrr.1115 Differs from OMIM 606973 reported by Jaeken et al. 2009; likely reflects table-level inconsistency or different entity mapping (gene vs disease), so should be verified against OMIM directly before KB ingestion.
Disease synonym — COG1-congenital disorders of glycosylation Salazar et al., 2021 (salazar2021cog1‐congenitaldisordersof pages 1-3) https://doi.org/10.1111/cge.13980 Modern gene-based disease naming used in Clinical Genetics.
Disease synonym — COG1-CDG Salazar et al., 2021 (salazar2021cog1‐congenitaldisordersof pages 1-3) https://doi.org/10.1111/cge.13980 Common short-form current nomenclature.
Historical CDG subtype name — CDG-IIg Wolfe & Krasnewich, 2013; Huang et al., 2021 (wolfe2013congenitaldisordersof pages 3-5, huang2021componentofoligomeric pages 1-2) https://doi.org/10.1002/ddrr.1115; https://doi.org/10.1186/s12887-021-02922-7 Historical subtype designation still used in reviews/case reports; often paired with COG1-CDG.
Historical proposed disease name — CDG-II Cog1 Foulquier et al., 2006 (foulquier2006conservedoligomericgolgi pages 1-2) https://doi.org/10.1073/pnas.0507685103 Original proposed naming in the first disease report: “We propose naming this disorder CDG-II Cog1”.
Disease description / synonym — CDG-II caused by Cog1 deficiency Foulquier et al., 2006 (foulquier2006conservedoligomericgolgi pages 1-2) https://doi.org/10.1073/pnas.0507685103 Original descriptive phrase from the discovery paper.
Disease synonym — Conserved oligomeric Golgi complex subunit 1 deficiency Foulquier et al., 2006 (foulquier2006conservedoligomericgolgi pages 1-2) https://doi.org/10.1073/pnas.0507685103 Title-based descriptive synonym from first report.
Disease synonym — COG1 deficiency Wolfe & Krasnewich, 2013; Huang et al., 2021 (wolfe2013congenitaldisordersof pages 3-5, huang2021componentofoligomeric pages 1-2) https://doi.org/10.1002/ddrr.1115; https://doi.org/10.1186/s12887-021-02922-7 Concise disease label frequently used in reviews and case literature.
Disease synonym — Component of oligomeric Golgi complex 1 deficiency Huang et al., 2021 (huang2021componentofoligomeric pages 1-2) https://doi.org/10.1186/s12887-021-02922-7 Modern article title wording; omits “conserved” but clearly refers to COG1-related deficiency.
Defective protein / gene product description — Component of conserved oligomeric Golgi complex 1 Jaeken et al., 2009 (j2009cdgnomenclaturetime pages 3-4) https://doi.org/10.1016/j.bbadis.2009.08.005 Useful as a normalized protein-level description rather than a disease name.
Identifier availability in gathered evidence Not reported Orphanet / MONDO / ICD-10 / ICD-11 / MeSH No supporting identifier in gathered evidence (j2009cdgnomenclaturetime pages 3-4, wolfe2013congenitaldisordersof pages 3-5, foulquier2006conservedoligomericgolgi pages 1-2, huang2021componentofoligomeric pages 1-2, salazar2021cog1‐congenitaldisordersof pages 1-3) — These identifiers were not present in the extracted evidence and should be looked up separately in authoritative databases rather than inferred.

Table: This table summarizes the key disease names, subtype labels, and reported OMIM identifiers for COG1-congenital disorder of glycosylation based only on gathered evidence. It also highlights an important OMIM-number discrepancy that should be reconciled before database entry.

Mondo ID: not available in the retrieved evidence excerpts and therefore not reported here.

1.3 Synonyms / alternative names

Commonly used names in the literature include COG1‑CDG, CDG‑IIg, COG1 deficiency, conserved oligomeric Golgi complex subunit 1 deficiency, and component of (conserved) oligomeric Golgi complex 1 deficiency. (j2009cdgnomenclaturetime pages 3-4, wolfe2013congenitaldisordersof pages 3-5, foulquier2006conservedoligomericgolgi pages 1-2, huang2021componentofoligomeric pages 1-2)

2. Etiology

2.1 Disease causal factors

Primary cause: biallelic (typically loss‑of‑function) variants in COG1 that impair COG complex function and thereby disrupt Golgi enzyme localization/stability and glycan processing, producing combined N‑ and O‑glycosylation defects. (foulquier2006conservedoligomericgolgi pages 3-4, foulquier2006conservedoligomericgolgi pages 2-3)

2.2 Risk factors

For this Mendelian disorder, the main risk factor is carrier status of pathogenic COG1 variants, with disease occurring in biallelic state; early cases included consanguinity. (foulquier2006conservedoligomericgolgi pages 2-3, foulquier2006conservedoligomericgolgi pages 3-4)

2.3 Protective factors / gene–environment interactions

No protective alleles or gene–environment interactions were identified in the retrieved evidence for COG1‑CDG specifically.

3. Phenotypes

3.1 Core phenotype spectrum (human clinical)

Across reported individuals, the phenotype is variable but commonly includes neurodevelopmental and multi‑system findings:

  • Neurodevelopment: developmental delay / global developmental delay, hypotonia, progressive microcephaly; neonatal seizures have been reported. (foulquier2006conservedoligomericgolgi pages 2-3, salazar2021cog1‐congenitaldisordersof pages 3-4, salazar2021cog1‐congenitaldisordersof pages 1-3)
  • Growth/feeding: feeding problems and failure to thrive in infancy, postnatal growth deficiency (variable). (foulquier2006conservedoligomericgolgi pages 2-3, salazar2021cog1‐congenitaldisordersof pages 3-4)
  • Dysmorphism/skeletal: facial dysmorphism; tibial bowing/curvature and other skeletal anomalies have been described; a subset had cerebrocostomandibular‑like syndrome with costovertebral dysplasia linked to a splice variant (c.1070+5G>A). (salazar2021cog1‐congenitaldisordersof pages 3-4, salazar2021cog1‐congenitaldisordersof pages 1-3)
  • Liver involvement: hepatitis and marked transaminase elevation can occur (e.g., AST up to 1108 U/L in one reported child). (salazar2021cog1‐congenitaldisordersof pages 3-4, salazar2021cog1‐congenitaldisordersof pages 1-3)
  • Endocrine/metabolic: neonatal and recurrent hypoglycemia was described in one case report. (huang2021componentofoligomeric pages 3-6)

Patient counts (reported in reviews/case reports): Salazar et al. (2021) states “COG1‑CDG has been reported in five patients.” (salazar2021cog1‐congenitaldisordersof pages 1-3)

3.2 Phenotype characteristics (onset, severity, progression)

  • Onset: typically congenital/neonatal for hypotonia, feeding difficulty, and (in some) seizures or hypoglycemia. (huang2021componentofoligomeric pages 3-6, salazar2021cog1‐congenitaldisordersof pages 1-3)
  • Course/progression: progressive microcephaly has been repeatedly noted; severity appears variant‑dependent, with c.1070+5G>A (splice) cases described as more severe multi‑organ disease in a review. (salazar2021cog1‐congenitaldisordersof pages 3-4)

3.3 Suggested HPO terms (non‑exhaustive; based on reported features)

  • Global developmental delay HP:0001263
  • Hypotonia HP:0001252
  • Seizures HP:0001250
  • Progressive microcephaly HP:0000253
  • Failure to thrive HP:0001508
  • Abnormality of the corpus callosum HP:0001273
  • Abnormal liver function tests / elevated transaminases HP:0002910
  • Hypoglycemia HP:0001943
  • Facial dysmorphism HP:0001999 (broad)
  • Tibial bowing HP:0002995

Frequency note: Quantitative per‑phenotype frequencies are not available from the retrieved evidence due to very small cohorts.

4. Genetic / molecular information

4.1 Causal gene

COG1 (component/subunit 1 of the conserved oligomeric Golgi complex). (j2009cdgnomenclaturetime pages 3-4, foulquier2006conservedoligomericgolgi pages 2-3)

4.2 Pathogenic variants (summarized)

Reported alleles include homozygous truncating variants (frameshift), splice‑site variants, and one compound heterozygous case including a missense variant. (foulquier2006conservedoligomericgolgi pages 3-4, huang2021componentofoligomeric pages 1-2, salazar2021cog1‐congenitaldisordersof pages 1-3)

Variant (HGVS; transcript if given) Zygosity Variant class Main reported clinical features Key biochemical diagnostic findings Source (paper, year) URL / DOI Notes
c.2659_2660insC in COG1 (older nomenclature in discovery paper); predicted frameshift from aa 888 with premature stop/truncated C-terminus Homozygous Frameshift, truncating, presumed loss-of-function First reported patient: feeding problems, failure to thrive, generalized hypotonia, small hands/feet, facial dysmorphism, rhizomelic short stature, progressive microcephaly, mild psychomotor retardation, mild hepatosplenomegaly (foulquier2006conservedoligomericgolgi pages 2-3, foulquier2006conservedoligomericgolgi pages 3-4, foulquier2006conservedoligomericgolgi pages 1-2) Type II serum transferrin IEF with reduction of penta-/hexasialotransferrin and increase of asialo-/mono-/di-/trisialotransferrin; abnormal ApoC-III with ApoC-III0 band; reduced incorporation of [3H]UDP-galactose and [3H]CMP-neuraminic acid; undersialylation/undergalactosylation of serum N-glycans (foulquier2006conservedoligomericgolgi pages 2-3) Foulquier et al., 2006 https://doi.org/10.1073/pnas.0507685103 Original discovery report; wild-type COG1 restored β1,4-galactosyltransferase localization; quantified Golgi enzyme decreases included 55% for mannosidase II and 67% for β1,4-galactosyltransferase I (foulquier2006conservedoligomericgolgi pages 3-4)
NM_018714.3: c.2665dup; p.(Arg889Profs*12) Homozygous Frameshift, truncating Neonatal multifocal clonic seizures, hypotonia, weakness, absent reflexes, feeding/swallowing disorder, developmental delay, progressive microcephaly, dysmorphic facial features, adducted thumbs, widely spaced nipples, tibial bowing/curvature, dysmorphic corpus callosum and frontal atrophy/thin corpus callosum on MRI, hepatitis/liver involvement; later milder course with independent gait at 1 year 10 months in one proband (salazar2021cog1‐congenitaldisordersof pages 1-3, salazar2021cog1‐congenitaldisordersof pages 3-4) Type II serum transferrin isoelectrofocusing pattern with increased trisialo-, disialo-, monosialo-, and asialo-transferrin and decreased tetrasialotransferrin; marked transaminase elevations reported (AST up to 1108 U/L, ALT 169 U/L) (salazar2021cog1‐congenitaldisordersof pages 3-4, salazar2021cog1‐congenitaldisordersof pages 1-3) Salazar et al., 2021 https://doi.org/10.1111/cge.13980 Review states COG1-CDG reported in 5 patients; same variant reported in at least 2 homozygous patients. gnomAD frequency reported as 6/251,390 alleles overall (heterozygous) and 5/34,590 alleles in Latino/Admixed American population in one summary (salazar2021cog1‐congenitaldisordersof pages 3-4, salazar2021cog1‐congenitaldisordersof pages 1-3)
c.1070+5G>A Homozygous Canonical/near-canonical splice donor variant causing exon 6 skipping, frameshift, premature stop in exon 7 Two patients with cerebrocostomandibular-like syndrome / severe multisystem COG1-CDG: prenatal growth impairment, hearing impairment, cryptorchidism, renal involvement, skeletal abnormalities including costovertebral dysplasia, delayed walking and speech; associated with more severe phenotype than c.2665dup cases (salazar2021cog1‐congenitaldisordersof pages 3-4, salazar2021cog1‐congenitaldisordersof pages 1-3) Not specifically detailed in the extracted Zeevaert evidence here; COG1-CDG in general shows type II glycosylation abnormalities and delayed retrograde trafficking in patient fibroblasts (foulquier2006conservedoligomericgolgi pages 1-2, reynders2009golgifunctionand pages 9-10) Zeevaert et al., 2009; summarized in Salazar et al., 2021 https://doi.org/10.1093/hmg/ddn379 ; https://doi.org/10.1111/cge.13980 Zeevaert abstract: intronic mutation disrupted splice donor, leaving only ~3% normal transcript in one patient and showing delay in retrograde trafficking by Brefeldin A assay (foulquier2006conservedoligomericgolgi pages 1-2); older patients in review were aged 12.5 and 14 years (salazar2021cog1‐congenitaldisordersof pages 3-4)
c.1070+3A>G Heterozygous in compound heterozygous state Splice-region variant In Huang case: recurrent cyanosis, poor responsiveness, neonatal hypoglycemia from day 2 of life, recurrent hypoglycemic episodes after discharge, developmental/motor retardation, epilepsy/convulsions, strabismus; literature review also notes dysmorphic and neurologic findings in COG1-CDG such as microcephaly and macular lesions (huang2021componentofoligomeric pages 3-6) Paper states patient was diagnosed as CDG-IIg; specific transferrin profile not extracted in gathered evidence for this row (huang2021componentofoligomeric pages 3-6) Huang et al., 2021 https://doi.org/10.1186/s12887-021-02922-7 Maternal allele in reported compound heterozygous proband; authors proposed hypoglycemia may relate to altered insulin secretion, but this remains speculative (huang2021componentofoligomeric pages 3-6)
c.2492G>A; p.(Arg831Gln) Heterozygous in compound heterozygous state Missense; proposed pathogenic / potential pathogenetic variant Same Huang proband as above: developmental retardation, convulsion/epilepsy, strabismus, neonatal and recurrent hypoglycemia (huang2021componentofoligomeric pages 1-2, huang2021componentofoligomeric pages 3-6) Paper states CDG-IIg diagnosis after genetic and clinical evaluation; specific glycosylation assay details were not extracted in gathered evidence (huang2021componentofoligomeric pages 1-2, huang2021componentofoligomeric pages 3-6) Huang et al., 2021 https://doi.org/10.1186/s12887-021-02922-7 Paternally inherited allele; authors state p.Arg831Gln “may be a potential pathogenetic variant” and that only a very small number of CDG-IIg cases had been reported previously (huang2021componentofoligomeric pages 1-2, huang2021componentofoligomeric pages 3-6)
NM_018714.3: c.1049C>T; p.(Thr350Met) Reported as homozygous in prior literature/database discussion Missense Evidence for pathogenicity is weak in gathered evidence; no specific clinical phenotype extracted for a confirmed affected case in the current evidence set (salazar2021cog1‐congenitaldisordersof pages 1-3) Not established from gathered evidence Salazar et al., 2021 https://doi.org/10.1111/cge.13980 Mentioned as the only reported missense in COG1, but also noted to be homozygous in gnomAD and therefore likely benign / uncertain rather than clearly pathogenic; included here for completeness and caution, not as a firmly established disease-causing allele (salazar2021cog1‐congenitaldisordersof pages 3-4, salazar2021cog1‐congenitaldisordersof pages 1-3)

Table: This table compiles the COG1-CDG/CDG-IIg variants supported by the gathered evidence, together with zygosity, variant class, phenotype, and diagnostic findings. It highlights the small number of reported pathogenic truncating/splice variants, the Huang compound-heterozygous case, and key biochemical hallmarks such as the type II transferrin profile.

4.3 Variant consequences and functional effects

The original COG1‑CDG patient had a homozygous frameshift insertion predicted to truncate COG1, and patient fibroblasts showed reduced Golgi localization/intensity of key processing enzymes (ManII and β1,4GalT1). (foulquier2006conservedoligomericgolgi pages 3-4)

A review case reported that NM_018714.3: c.2665dup; p.(Arg889Profs*12) occurs at very low allele frequency in gnomAD in heterozygous state (6/251,390 alleles). (salazar2021cog1‐congenitaldisordersof pages 3-4)

4.4 Modifier genes / epigenetics / chromosomal abnormalities

No validated modifier genes, epigenetic alterations, or recurrent chromosomal abnormalities were identified for COG1‑CDG in the retrieved evidence.

5. Environmental information

COG1‑CDG is a monogenic disorder; the retrieved evidence does not identify environmental triggers that cause disease. However, diagnostic workups caution that secondary causes can mimic abnormal transferrin glycosylation patterns and should be excluded (e.g., galactosemia, hereditary fructose intolerance, alcoholism). (jaeken2011congenitaldisordersof pages 2-4, goreta2012insightsintocomplexity pages 6-7)

6. Mechanism / pathophysiology

6.1 Current mechanistic understanding (causal chain)

Upstream defect: loss of COG1 disrupts COG complex integrity and its role as a tethering/trafficking regulator for intra‑Golgi retrograde vesicles, which is needed to maintain correct localization and stability of Golgi glycosylation enzymes. (foulquier2006conservedoligomericgolgi pages 2-3, reynders2011howgolgiglycosylation pages 6-7, pokrovskaya2011conservedoligomericgolgi pages 1-2)

Cellular consequences: altered Golgi trafficking and enzyme mislocalization/destabilization lead to defective glycan processing across cisternae, producing combined N‑ and O‑glycosylation abnormalities. (foulquier2006conservedoligomericgolgi pages 2-3, foulquier2006conservedoligomericgolgi pages 3-4, reynders2011howgolgiglycosylation pages 6-7)

Quantified example (patient fibroblasts): In the discovery patient, immunofluorescence quantification showed Golgi ManII intensity ~55% of control and β1,4GalT1 ~33% of control (i.e., a 67% decrease), consistent with impaired glycan maturation. (foulquier2006conservedoligomericgolgi pages 3-4, foulquier2006conservedoligomericgolgi media 6ea0c8a8)

6.2 Biochemical abnormalities

A characteristic hallmark is a type 2 serum transferrin isoelectric focusing (TIEF) pattern, reflecting defective glycan processing/sialylation. (foulquier2006conservedoligomericgolgi pages 2-3, salazar2021cog1‐congenitaldisordersof pages 1-3)

Direct quote (abstract-level diagnostic criterion): Salazar et al. describe COG1‑CDG with “a type 2 serum transferrin isoelectrofocusing.” (salazar2021cog1‐congenitaldisordersof pages 1-3)

ApoC‑III abnormalities can indicate O‑glycosylation involvement; the discovery COG1 patient had an abnormal ApoC‑III profile with an ApoC‑III0 band. (foulquier2006conservedoligomericgolgi pages 2-3)

6.3 Suggested ontology terms

GO biological process (examples): * Golgi vesicle transport GO:0048193 * Retrograde transport, Golgi to ER / intra‑Golgi retrograde transport (general) GO:0006890 (broader retrograde processes) * Protein glycosylation GO:0006486

GO cellular component: * Golgi apparatus GO:0005794

Cell Ontology (CL) candidates (based on affected systems; evidence indirect): neurons (CL:0000540), hepatocytes (CL:0000182).

7. Anatomical structures affected

Based on reported multi‑system disease:

  • Central nervous system (UBERON:0001017): developmental delay, seizures, brain MRI abnormalities (corpus callosum, atrophy). (salazar2021cog1‐congenitaldisordersof pages 3-4, salazar2021cog1‐congenitaldisordersof pages 1-3)
  • Liver (UBERON:0002107): hepatitis and elevated transaminases. (salazar2021cog1‐congenitaldisordersof pages 3-4, salazar2021cog1‐congenitaldisordersof pages 1-3)
  • Skeletal system (UBERON:0001434): tibial curvature and (in severe cases) costovertebral anomalies. (salazar2021cog1‐congenitaldisordersof pages 3-4, salazar2021cog1‐congenitaldisordersof pages 1-3)

Subcellular localization: Golgi apparatus dysfunction is central. (foulquier2006conservedoligomericgolgi pages 2-3, reynders2011howgolgiglycosylation pages 6-7)

8. Temporal development

  • Typical onset: congenital/neonatal (feeding issues, hypotonia; sometimes seizures/hypoglycemia). (huang2021componentofoligomeric pages 3-6, salazar2021cog1‐congenitaldisordersof pages 1-3)
  • Progression: progressive microcephaly and evolving neuroimaging findings have been described. (salazar2021cog1‐congenitaldisordersof pages 3-4, salazar2021cog1‐congenitaldisordersof pages 1-3)

Formal staging systems are not available for this ultra‑rare condition.

9. Inheritance and population

9.1 Inheritance

COG1‑CDG is reported as autosomal recessive with biallelic variants (homozygous or compound heterozygous). (foulquier2006conservedoligomericgolgi pages 3-4, salazar2021cog1‐congenitaldisordersof pages 1-3)

9.2 Epidemiology

No prevalence/incidence estimates specific to COG1‑CDG were identified in the retrieved evidence. Reviews emphasize the extremely small number of reported cases. (salazar2021cog1‐congenitaldisordersof pages 1-3, huang2021componentofoligomeric pages 1-2)

10. Diagnostics

10.1 Biochemical testing

First-line screen: serum transferrin isoelectric focusing (TIEF) remains an established first‑line biochemical screen for CDG. (jaeken2011congenitaldisordersof pages 2-4, mohamed2011clinicalanddiagnostic pages 1-2)

Type 2 pattern in COG1‑CDG: increased asialo/mono/di/tri‑sialotransferrin with reduced tetra/penta/hexa forms (pattern shown visually in the original report). (foulquier2006conservedoligomericgolgi pages 2-3, foulquier2006conservedoligomericgolgi media 1a96ba21)

O‑glycosylation adjunct: ApoC‑III IEF can be used to assess O‑glycan abnormalities in suspected combined defects. (mohamed2011clinicalanddiagnostic pages 2-3, jaeken2011congenitaldisordersof pages 2-4)

Follow-up/omics: serum N‑glycan mass spectrometry can identify signatures reported for COG defects such as decreased sialylation and undergalactosylation/other processing abnormalities. (guillard2012biochemicalandclinical pages 18-22)

10.2 Genetic testing approach

Given limitations in delineating the primary defect biochemically in many type 2 TIEF patients, molecular testing is central; diagnostic reviews describe targeted mutation analysis of COG1–COG8 among candidate genes for type 2 patterns when supported by complementary assays and phenotype. (mohamed2011clinicalanddiagnostic pages 2-3, goreta2012insightsintocomplexity pages 7-9)

10.3 Differential diagnosis / mimics

Secondary causes or confounders of transferrin glycosylation abnormalities that should be excluded include galactosemia, hereditary fructose intolerance, alcoholism, and transferrin variants. (jaeken2011congenitaldisordersof pages 2-4, goreta2012insightsintocomplexity pages 6-7)

11. Outcome / prognosis

The small number of reported patients and strong variant dependence limit prognosis generalization. Reviews suggest that homozygous splice‑site cases (c.1070+5G>A) are associated with more severe, multisystem involvement than some truncating cases, but robust survival statistics are not available in the retrieved evidence. (salazar2021cog1‐congenitaldisordersof pages 3-4)

12. Treatment

12.1 Disease-modifying therapy

No COG1‑CDG‑specific disease‑modifying therapy was identified in the retrieved evidence.

12.2 Supportive/symptomatic management (real-world implementation)

  • Hypoglycemia management: one reported infant with COG1‑CDG and hypoglycemia improved after glucose infusion. (huang2021componentofoligomeric pages 1-2)
  • Seizure management: neonatal seizures were treated with standard antiseizure medications in one case (phenobarbital/levetiracetam), with early seizure control reported. (salazar2021cog1‐congenitaldisordersof pages 1-3)

Suggested MAXO terms (examples): * Glucose supplementation MAXO:0000747 (conceptual mapping) * Antiepileptic therapy MAXO:0000558 (conceptual mapping) * Genetic counseling MAXO:0000127 (conceptual mapping)

12.3 Clinical trials

No COG1‑CDG‑specific interventional trials were found. The retrieved trial corpus includes CDG trials for other gene‑specific CDGs (e.g., PMM2‑CDG, DHDDS‑CDG), but these are not directly applicable to COG1‑CDG. (NCT07572825 chunk 1, NCT04925960 chunk 1)

13. Prevention

Primary prevention is not applicable in the usual public‑health sense for this monogenic disorder; prevention focuses on reproductive risk reduction:

  • Carrier testing / cascade testing in families once a pathogenic COG1 genotype is identified. (foulquier2006conservedoligomericgolgi pages 3-4)
  • Prenatal diagnosis / preimplantation genetic testing are logically enabled by known familial variants, though specific COG1‑CDG pregnancy series were not present in the retrieved evidence.

14. Other species / natural disease

No naturally occurring veterinary disease analogs for COG1 deficiency were identified in the retrieved evidence.

15. Model organisms and experimental systems

  • Patient-derived fibroblasts: used to quantify Golgi enzyme localization deficits and to demonstrate rescue of β1,4‑galactosyltransferase localization by wild‑type COG1 expression. (foulquier2006conservedoligomericgolgi pages 3-4)
  • Brefeldin A (BFA) trafficking assays: used across COG‑CDGs to demonstrate retrograde trafficking defects; these assays are reported as revealing retrograde defects in COG‑deficient cells. (reynders2009golgifunctionand pages 9-10, pokrovskaya2011conservedoligomericgolgi pages 1-2)
  • CHO cell mutants (COG1/ldlB): used to study glycosylation and trafficking phenotypes attributable to COG1 loss. (smith2008roleofthe pages 4-5)

Dedicated vertebrate models (mouse/zebrafish) specifically for COG1‑CDG were not identified in the retrieved evidence.

Recent developments (2023–2024) and contextual statistics

Although COG1‑CDG itself has few new case series in 2023–2024 in the retrieved corpus, recent reviews provide important context:

  • CDG field scale (2024): an immunopathology review states CDG comprise “more than 160 rare and complex genetic diseases” and summarizes immune involvement across 12 CDGs with major immune manifestations (not COG1‑specific). (pascoal2024revisitingtheimmunopathology pages 1-2)
  • Cardiac manifestations across carbohydrate‑linked IMDs (2023): a systematic review reports “We identified 58 IMDs presenting with cardiac complications” and lists COG1 among “29 congenital disorders of glycosylation” associated with cardiac complications, supporting cardiac surveillance as a general consideration for CDG (not COG1‑specific penetrance). (conte2023metaboliccardiomyopathiesand pages 1-2)

Visual evidence (primary report)

The original COG1‑CDG report includes a transferrin IEF figure demonstrating the type II pattern and a figure quantifying reduced Golgi ManII and β1,4GalT1 localization in patient fibroblasts. (foulquier2006conservedoligomericgolgi media 1a96ba21, foulquier2006conservedoligomericgolgi media 6ea0c8a8)

Key limitations of current evidence

  1. Ultra-rare case count limits phenotype frequency estimates, genotype–phenotype correlations, and evidence-based prognosis. (salazar2021cog1‐congenitaldisordersof pages 1-3, huang2021componentofoligomeric pages 1-2)
  2. Identifier gaps: Orphanet/MONDO/ICD/MeSH codes were not present in retrieved excerpts; OMIM identifiers differed between two secondary tables and should be verified directly in OMIM prior to KB finalization. (j2009cdgnomenclaturetime pages 3-4, wolfe2013congenitaldisordersof pages 3-5)
  3. Therapeutics: no COG1‑targeted clinical trials or disease-modifying therapies were identified; management remains symptomatic/supportive. (huang2021componentofoligomeric pages 1-2)

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